Polymicrobial infections often include pathogens that produce beta-lactamase enzymes. These enzymes commonly cause resistance to penicillins and cephalosporins. Without treatment these enzymes would multiply and thrive unimpeded, with serious or critical consequences to the patient.
To treat such infections, a product consisting of piperacillin sodium and tazobactam sodium in an 8 to 1 ratio (as free acids), is currently marketed under the tradename Zosyn.RTM.. This product is disclosed in U.S. Pat. No.4,562,073 to Micetich et al. However, because piperacillin is inherently unstable in solution at room temperature, like most penicillin compounds, Wyeth-Ayerst Research developed Zosyn.RTM. as a lyophilized vial product where the piperacillin is stored in the solid state.
In use, the piperacillin component offers the safety and efficacy of a broad-spectrum beta-lactam antibiotic. U.S. Pat. Nos. 4,477,452 and 4,534,977, both to Haeger, disclose a lyophilized form of piperacillin. Tazobactam reduces the vulnerability of the piperacillin to the bacteria that produce beta-lactamase enzymes. Basically, the tazobactam permanently inactivates beta-lactamases, allowing the piperacillin component to destroy susceptible bacteria. However, Zosyn.RTM. is supplied in a lyophilized form and therefore must be reconstituted prior to intravenous administration.
Zosyn.RTM. is a relatively potent antibiotic. It is used for the treatment of moderate to severe infections caused by piperacillin-resistant, piperacillin/tazobactam-susceptible beta-lactamase-producing strains of microorganisms in conditions such as nosocomial pneumonia due to Staphylococcus aureits; intra-abdominal infections, specifically appendicitis (complicated by rupture or abscess) and peritonitis due to Escherichia coli, skin and skin structure infections, including cellulitits, cutaneous abscesses and ischemic/diabetic foot infections due to Staphylococcus acreus; and gynecologic infections, specifically postpartum endometritis or pelvic inflammatory disease due to Escherichia coli. The seriousness of these infections highlights the need for a readily available and dependable treatment.
The admixing required by the lyophilized vial product is a skilled pharmaceutical procedure that must be performed using aseptic techniques to ensure product quality. This step creates the possibility of contamination and dosage miscalculation. It also adds to the cost of preparing the Zosyn.RTM. for administration. The laborious and difficult technique of lyophilizing and reconstituting the drug is addressed in U.S. Pat. No. 5,763,603 to Trickes. While the Trickes reference does teach a process of increasing the stability of tazobactam, such is accomplished by crystallization rather than in a buffered pH solution.
Another drawback of the reconstituted product is reflected in its short refrigerated shelf life. The reconstituted product remains stable and commercially viable for only seven days while refrigerated according to the manufacturer's product labeling (See also Physicians' Desk Reference, Medical Economics Company, Inc., pp. 1434-37 (52 ed., 1998)). The short shelf life and the reconstitution step may also lead to increased waste disposal as the components required to prepare the reconstituted solution, such as vials, needles and bags, as well as unused portions of the product, must be properly discarded.
Finally, another concern with the lyophilized powder vial product is that after reconstitution it has a pH more acidic than 6.5. This acidic condition increases the potential for hemolysis and pain to the patient during infusion.
The formulations of the present invention overcome the disadvantages of the reconstituted product as they are premixed and stable for longer periods at refrigerated temperature. Additionally, any potential for problems of contamination, needle sticks, increased waste, and dosage calculation errors are avoided, as medical personnel can simply use a prepared bag of the present formulations.